Discovery of the SHP2 allosteric inhibitor 2-((3R,4R)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(2,3-dichlorophenyl)-3-methylpyrrolo[2,1-f][1,2,4] triazin-4(3H)-one.

The non-receptor protein tyrosine phosphatase (PTP) SHP2 encoded by the PTPN11 gene is a critical regulator in a number of cellular signalling processes and pathways, including the MAPK and the immune-inhibitory programmed cell death PD-L1/PD-1 pathway. Hyperactivation and inactivation of SHP2 is of great therapeutic interest for its association with multiple developmental disorders and cancer-related diseases. In this work, we characterised a potent SHP2 allosteric inhibitor 2-((3 R,4R)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(2,3-dichlorophenyl)-3-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (PB17-026-01) by using structure-based design. To study the structure-activity relationship, we compared co-crystal structures of SHP2 bound with PB17-026-01 and its analogue compound PB17-036-01, which is ∼20-fold less active than PB17-026-01, revealing that both of the compounds are bound to SHP2 in the allosteric binding pocket and PB17-026-01 forms more polar contacts with its terminal group. Overall, our results provide new insights into the modes of action of allosteric SHP2 inhibitor and a guide for the design of SHP2 allosteric inhibitor.

Green merger and acquisition decision driven by environmental regulation and its impact on green innovation: evidence from Chinese heavily polluting listed enterprises.

How heavily polluting enterprises achieve sustainable development has become an urgent issue to be solved. Based on the data of Chinese heavily polluting listed enterprises during the period of 2010-2020, this paper adopts the probit method to examine how heterogeneous environmental regulations affect green merger and acquisition (GMA) decision, and propensity score matching and difference-in-differences method to explore innovation performance of GMA. The findings are as follows: (1) Command-and-control environmental regulation (CMCER) can promote GMA, while there exists a U-shaped relationship between market-based environmental regulation (MBER) and GMA; (2) from a dynamic perspective, it turns out that GMA can promote green innovation (GI) in the first and second post-acquisition year, but this effect disappears in the third year; (3) compared with CMCER, MBER has a more pronounced positive effect on the relationship between GMA and GI; (4) heterogeneous analysis indicates that the above GMA performance is more persistent when the acquirer is state-owned, with high media attention, with high internal control or engages in vertical GMA. The findings further enrich the literature on GMA driver and performance and provide references for optimizing ER policies and promoting corporate sustainable development.

Physiological adaptation of Cyperus esculentus L. seedlings to varying concentrations of saline-alkaline stress: Insights from photosynthetic performance.

Soil salinization effects plant photosynthesis in a number of global ecosystems. In this study, photosynthetic and physiological parameters were used to elucidate the impacts of saline-alkaline stress on Cyperus esculentus L. (C. esculentus) seedling photosynthesis. The results demonstrate that salt stress, alkali stress and mixed salt and alkali stress treatments all have similar bell-shaped influences on photosynthesis. At low concentrations (0-100 mmol L-1), saline-alkaline stress promoted net photosynthetic rate, transpiration rate and water use efficiency in C. esculentus. However, as the treatments increased in intensity (100-200 mmol L-1), plant photosynthetic parameters began to decline. We interpreted this as the capacity of C. esculentus to improve osmoregulatory capacity in low saline-alkaline stress treatments by accumulating photosynthetic pigment, proline and malondialdehyde to counterbalance the induced stress - an adaptive mechanism that failed once concentrations reached a critical threshold (100 mmol L-1). Stomatal conductance, maximum photosynthetic rate and actual photosynthetic rate all decreased with increasing concentration of the stress treatments, and intercellular carbon dioxide showed a decreasing and then increasing trend. These results indicated that when the saline-alkaline stress concentrations were low, C. esculentus seedlings showed obvious adaptive ability, but when the concentration increased further, the physiological processes of C. esculentus seedlings were significantly affected, with an obvious decrease in photosynthetic efficiency. This study provides a new understanding of the photosynthetic adaptation strategies of C. esculentus seedlings to varying concentrations of saline-alkaline stress.

Study on the Cooling Performance of a Focused Ultrasonic Radiator for Electrical Heating Elements.

In this work, a focused ultrasonic radiator is proposed for cooling the electrical heating elements in the focal region, and its working characteristics are investigated. The analyses of the FEM computational and flow field visualization test results indicate that focused ultrasound can generate forced convective heat transfer by the acoustic streaming in the focal region, which can cool the heating elements effectively. Experiments show that when the input voltage is 30Vp-p and the ambient temperature is 25 °C, the focused ultrasonic radiator can cause the surface temperature of the heating element (high-temperature alumina ceramic heating plate with a diameter of 5 mm) in the focal region to drop from 100 °C to about 55 °C. When the diameter of the electrical heating element is changed from 5 mm to 30 mm, the cooling effect is similar in the focal region. Compared with a fan, the focused ultrasound radiator has a shorter cooling time and a more concentrated cooling area. The focused ultrasonic radiator proposed in this work is suitable for some special environments.

Near-Infrared Light-Driving Organic Photothermal Agents with an 88.9% Photothermal Conversion Efficiency for Image-Guided Synergistic Phototherapy.

Photothermal agents (PTAs) with desirable near-infrared (NIR) absorption and excellent photothermal conversion efficiency (PCE) are ideal candidates for cancer treatment. However, numerous PTAs still require high-intensity and long-duration laser irradiation to completely ablate the tumor during the photothermal therapy (PTT) process, resulting in light damage to healthy skin and tissue as well as limiting their biomedical applications. Integrating intense NIR absorption and high PCE into a single small-molecule PTA is an important prerequisite for realizing efficient PTT, but is a serious challenge. Herein, a series of donor-acceptor type PTAs (CC1 to NC4) are designed through a molecular engineering strategy. Theoretical calculations and experimental results show that the NIR absorption and photothermal effect from CC1 to NC4 are significantly enhanced as expected. Notably, NC4 nanoparticles exhibit intense NIR absorption, superhigh PCE of up to 88.9% for PTT, photoacoustic imaging and photothermal imaging, and effective reactive oxygen species generation for photodynamic therapy (PDT). The superior PTT/PDT synergistic phototherapeutic efficacy is well demonstrated by the complete elimination of tumor in vivo upon one-time, low-intensity, and short-duration laser irradiation (808 nm, 330 mW cm-2, and 3 min). This work provides a valuable guideline for rational design of PTAs for cancer phototherapy.

Acceptor-donor-acceptor type organic photothermal agents with enhanced NIR absorption and photothermal conversion effect for cancer photothermal therapy.

Numerous photothermal agents (PTAs) require high-intensity and long-duration laser excitation for photothermal therapy (PTT), resulting in light damage to healthy skin and tissue as well as limiting their biomedical applications. Integrating desirable near-infrared (NIR) absorption and high photothermal conversion efficiency (PCE) into a single small-molecule PTA is an important prerequisite for realizing efficient PTT, but is a serious challenge. Herein, through molecular engineering strategy, an acceptor-donor-acceptor (A-D-A) type PTA (ADA3) was readily developed for 808 nm laser-driving photothermal imaging and PTT of tumor. Theoretical calculations and experiment results show molecular engineering strategy is significant in regulating the structure and energy gap of PTAs, so as to effectively induce a narrow band gap for NIR absorption and further optimize photothermal properties. ADA3 possesses molar extinction coefficient of 3.1 × 104 M-1 cm-1 at 808 nm, followed being assembled into nanoparticles, ADA3-NPs show high PCE of 80.3%. In vivo experiments indicate that ADA3-NPs have excellent antitumor capability under one-time, low-intensity and short-duration (808 nm, 330 mW/cm2, 3 min) laser irradiation. Therefore, this work definitely exemplifies the enormous potential of molecular engineering strategy and provides an effective method for developing small-molecule PTAs.

Lin28 affects the proliferation and osteogenic differentiation of human dental pulp stem cells by directly inhibiting let-7b maturation.

OBJECTIVE: Activation of Lin28 gene under certain conditions promotes tissue damage repair. However, it remains unknown whether conditional expression of Lin28 facilitates the recovery of damaged pulp tissue. In the study, we focus on exploring the effects and possible regulatory mechanisms of Lin28 on the proliferation and differentiation of human dental pulp stem cells (hDPSCs). MATERIALS AND METHODS: We adopted techniques such as the ethynyl-2'-deoxyuridine (EdU) incorporation assay, RNA-protein immunoprecipitation (RIP) analysis, and luciferase assays to study the regulation of hDPSCs by Lin28. Furthermore, gain-of-function and loss-of-function analyses were also used in explored factors regulating hDPSCs activation. RESULTS: The results show that Lin28 inhibited osteogenic differentiation by directly targets pre-let-7b. Through bioinformatics sequencing and dual luciferase experiments we learned that let-7b directly targets the IGF2BP2 3'UTR. Silencing of IGF2BP2 showed a similar biological effect as overexpression of let-7b. Overexpression of IGF2BP2 counteracted the differentiation-promoting effects produced by let-7b overexpression. DISCUSSION/CONCLUSIONS: In conclusion, the RNA-binding protein Lin28 regulates osteogenic differentiation of hDPSCs by inhibiting let-7 miRNA maturation. And mature let-7b directly regulated the expression of IGF2BP2 by targeting the 3'UTR region of IGF2BP2 mRNA thus further inhibiting the differentiation of hDPSCs.

Design and Experiment of a Clamping-Drive Alternating Operation Piezoelectric Actuator.

In recent years, piezoelectric actuators, represented by inertial and inchworm actuators, have been widely applied because of their high accuracy and excellent responsiveness. Despite the development of various piezoelectric actuators, there remain some flaws in this technology. The sticking point is that the piezoelectric actuators based on the friction driving principle are prone to unwanted backward motion when outputting stepping motion. It is thus urgent to explore solutions from the perspectives of principle and structure. In this paper, a clamping-drive alternating operation piezoelectric actuator is proposed, the two feet of which are driven by two piezoelectric stacks, respectively. Due to double-foot alternate drive guide movement, backward movement is prevented in theory. By adopting the double-layer stator structure, integrated processing and assembly are facilitated. Meanwhile, a double flexible hinge mechanism is installed in the stator to prevent the drive foot from being overturned due to ineffectiveness and premature wear. In addition, the stator is equipped with the corresponding preload mechanism and clamping device. After the cycle action mechanism of one cycle and four steps is expounded, a model is established in this study to further demonstrate the principle. With the prototype produced, a series of experiments are performed. In addition, the amplitude of actuation of the stator is tested through amplitude experiment. The performance of the stator is evaluated by conducting experiments in the alternating step and single step actuation modes. Finally, the test results are analyzed to conclude that the actuator operating in either of these two modes can meet the practical needs of macro and micro actuation.

Quasi-Synchronization of Discrete-Time-Delayed Heterogeneous-Coupled Neural Networks via Hybrid Impulsive Control.

This article explores the quasi-synchronization of discrete-time-delayed heterogeneous-coupled neural networks (CNNs) via hybrid impulsive control. By introducing an exponential decay function, two non-negative regions are introduced that are named time-triggering and event-triggering regions, respectively. The hybrid impulsive control is modeled by the dynamical location of Lyapunov functional in two regions. When the Lyapunov functional locates in the time-triggering region, the isolated neuron node releases impulses to corresponding nodes in a periodical manner. Whereas, when the trajectory locates in the event-triggering region, the event-triggered mechanism (ETM) is activated, and there are no impulses. Under the proposed hybrid impulsive control algorithm, sufficient conditions are derived for quasi-synchronization with a definite error convergence level. Compared with pure time-triggered impulsive control (TTIC), the proposed hybrid impulsive control method can effectively reduce the times of impulses and save communication resources on the premise of ensuring performance. Finally, an illustrative example is given to verify the validity of the proposed method.

Reduced adsorption of norfloxacin on UV aging microplastics in anoxic environment.

Over recent years, much attention has been paid to aging problem of microplastics and adsorption behavior of antibiotic on microplastics. In this study, four microplastics, including polystyrene (PS), polypropylene (PP), polyamide (PA) and polyethylene (PE), were photoaged by UV light in anoxic environment. The surface characteristics of microplastics and adsorption behavior of norfloxacin (NOR) on microplastics were investigated. Results indicated that the specific surface area and crystallinity increased, and hydrophobicity weakened of microplastics after UV aging. The content of C element decreased and the content of O barely changed in the aged microplastics. In addition, the adsorption of NOR on microplastics yielded a better fitness for the pseudo-second-order kinetics, Langmuir and Freundlich models. The adsorption capacities of NOR on PS, PA, PP, and PE at 288 K were 16.01, 15.12, 14.03, and 13.26 mg·g-1, respectively, while the adsorption capacities of NOR on aged microplastics were reduced to 14.20, 14.19, 11.50, and 10.36 mg·g-1, respectively, due to decrease of hydrophobicity and increase of crystallinity of microplastics after UV aging. The adsorption of NOR on microplastics decreased with the increase of temperature, implying the adsorption process was exothermic. Adsorption mechanism analysis showed that Van der Waals force was the main influential mechanism of the adsorption of NOR on PP and PE, and hydrogen bond was the main factor affecting the adsorption of NOR on PA, while the π-π interaction was the main mechanism impacting the adsorption of NOR on PS. Aging time and salinity significantly affect the adsorption of NOR on microplastics. With the increase of humic acid concentration and pH, the adsorption of NOR on microplastics first reduced and then rose. This study provides a basis for further clarifying the mechanism of UV aging microplastics and a reference for the study of combined pollution behavior of microplastics and antibiotics.

The effective path of green transformation of heavily polluting enterprises promoted by green merger and acquisition-qualitative comparative analysis based on fuzzy sets.

Green merger and acquisition (GMA) is becoming a growing tendency for heavily polluting enterprises in recent years; however, the realization path of green transformation through GMA is still unexplored. Taking 48 Chinese heavily polluting enterprises that had GMA in 2018 as the research object, this paper constructs the "M&A attributes, Organizational characteristics, and External environment" (M-O-E) framework, by using the method of fuzzy-set qualitative comparative analysis (fsQCA) to reveal the configurations of conditions that lead to high levels of green innovation performance. The results show that the high green technology innovation performance after GMA of heavily polluting enterprises is the outcome of multiple antecedents, and no singular antecedent is sufficient for achieving it. Besides, there are three equivalent configurations of conditions to achieve green transformation: professional buyer, internal leading, and internal-external linkage. Among them, the professional buyer configuration highlights that the combination of M&A experience and M&A scale is of great importance, the internal leading configuration emphasizes that the existence of environmental awareness and organizational resources is the core conditions, and the internal-external linkage configuration requires simultaneous efforts of M&A experience and government environmental regulations. Our research contributes to the understanding of green transformation in heavily polluting enterprises from a configurational perspective, and provides a practice-oriented guide to achieve green transformation for the government and heavily polluting enterprises.

Structures of the CcmABCD heme release complex at multiple states.

Cytochromes c use heme as a cofactor to carry electrons in respiration and photosynthesis. The cytochrome c maturation system I, consisting of eight membrane proteins (CcmABCDEFGH), results in the attachment of heme to cysteine residues of cytochrome c proteins. Since all c-type cytochromes are periplasmic, heme is first transported to a periplasmic heme chaperone, CcmE. A large membrane complex, CcmABCD has been proposed to carry out this transport and linkage to CcmE, yet the structural basis and mechanisms underlying the process are unknown. We describe high resolution cryo-EM structures of CcmABCD in an unbound form, in complex with inhibitor AMP-PNP, and in complex with ATP and heme. We locate the ATP-binding site in CcmA and the heme-binding site in CcmC. Based on our structures combined with functional studies, we propose a hypothetic model of heme trafficking, heme transfer to CcmE, and ATP-dependent release of holoCcmE from CcmABCD. CcmABCD represents an ABC transporter complex using the energy of ATP hydrolysis for the transfer of heme from one binding partner (CcmC) to another (CcmE).

Numerical investigation of Miller cycle with EIVC and LIVC on a high compression ratio gasoline engine.

Previous studies have shown that increase compression ratio (CR) is an effective way to improve thermal efficiency of gasoline engine without changing the mechanical structure and working cycle, however, it is limited by engine knock when increasing the intake boosting under high load operation. This study aimed to solve the knock problem of gasoline engine with higher CR by application of Miller cycle, which can be implemented by either early or late intake valve closing (EIVC or LIVC). Therefore, in this paper, based on the engine with CR of 13.5 and electromagnetic valves train (EMVT), a comparative study was carried out to investigate the effects of EIVC and LIVC on engine performance, by theoretical modeling and calculation. The results show that, at high load, EIVC strategy is more preferred than LIVC owing to its lower total power consumption, which can improve the indicated mean effective pressure (IMEP) by 0.0371 bar, while enhance turbulence intensity and improve combustion. And at part load, the advantage for EIVC declines gradually, nevertheless, it can still sensitively adjust the EGR rate and thus reduce NOx. This results of quantitative analysis about two Miller cycles can provide valuable reference for engine designers and researchers.

Design, Analysis and Experiment of a Bridge-Type Piezoelectric Actuator for Infrared Image Stabilization.

Piezoelectric actuators are widely used in the optical field due to their high precision, compact structure, flexible design, and fast response. This paper presents a novel piezoelectric actuator with a bridge-type mechanism, which can be used to stabilize the images of an infrared imaging system. The bridge amplification mechanism is used to amplify the actuation displacement, and its structural parameters are optimized by the response surface method. The control strategy of the image stabilization system is formulated, and the overall structure of the infrared image stabilization system is designed according to the principle of image stabilization and the control strategy. The prototype was fabricated and verified by a series of experiments. In the test, the laminated piezoelectric ceramics are used as the driving element, and its maximum output displacement was about 17 µm under a voltage of 100 V. Firstly, the performance of the piezoelectric amplification mechanism was tested, and the maximum displacement of the piezoelectric micro-motion mechanism was 115 µm. The displacement amplification ratio of the mechanism was 5.7. Then, the step distance and response time of the micro-displacement mechanism were measured by inputting the stepping signal. When the input voltage increased to 3 V, 5 V, and 7 V, the stepping displacements of the mechanism were 2.4 µm, 4.1 µm, and 5.8 µm. Finally, the image stabilization effect of the designed mechanism was verified by imaging timing control and feedback signal processing.

Design, Analysis and Experiment of the Fiber Push-Out Device Based on Piezoelectric Actuator.

In this study, a fiber push-out device based on a piezoelectric actuator was designed, analyzed and tested, and its experimental environment was designed. The piezoelectric actuator includes a flexible beam. By using response surface analysis (RSM), taking the large displacement as the objective function and on the premise of meeting the strength requirements, the structural parameters of the flexible beam were analyzed. In the process of fiber push-out, the interfacial shear stress was estimated by establishing the system integrating the fiber-matrix-composite three-phase model and the piezoelectric actuator model using the analytic method, and the theoretical analysis results of the fiber interface mechanical properties were given. A prototype of the system was made, and the performance tests of the piezoelectric actuator and the fiber push-out device were carried out. The test results showed that the designed piezoelectric actuator can achieve a stepping resolution of 6.67 µm and a maximum displacement of about 100 µm at the input voltage of 150 V, which is consistent with the design results. The extrusion test of a single fiber was carried out using a piezoelectric actuator. The mechanical properties of the interfacial layer during the push-out process were measured and the interfacial shear strength was calculated, which is consistent with the theoretical analysis results. Finally, based on the mechanical properties obtained from the test, the loading failure process of the fiber was simulated by finite element analysis, which well explained the failure process of the fiber, thus verifying the feasibility of the designed fiber push-out device.

Design, Analysis, and Experiment on a Novel Stick-Slip Piezoelectric Actuator with a Lever Mechanism.

A piezoelectric actuator using a lever mechanism is designed, fabricated, and tested with the aim of accomplishing long-travel precision linear driving based on the stick-slip principle. The proposed actuator mainly consists of a stator, an adjustment mechanism, a preload mechanism, a base, and a linear guide. The stator design, comprising a piezoelectric stack and a lever mechanism with a long hinge used to increase the displacement of the driving foot, is described. A simplified model of the stator is created. Its design parameters are determined by an analytical model and confirmed using the finite element method. In a series of experiments, a laser displacement sensor is employed to measure the displacement responses of the actuator under the application of different driving signals. The experiment results demonstrate that the velocity of the actuator rises from 0.05 mm/s to 1.8 mm/s with the frequency increasing from 30 Hz to 150 Hz and the voltage increasing from 30 V to 150 V. It is shown that the minimum step distance of the actuator is 0.875 µm. The proposed actuator features large stroke, a simple structure, fast response, and high resolution.

Are My EHRs Private Enough? Event-Level Privacy Protection.

Privacy is a major concern in sharing human subject data to researchers for secondary analyses. A simple binary consent (opt-in or not) may significantly reduce the amount of sharable data, since many patients might only be concerned about a few sensitive medical conditions rather than the entire medical records. We propose event-level privacy protection, and develop a feature ablation method to protect event-level privacy in electronic medical records. Using a list of 13 sensitive diagnoses, we evaluate the feasibility and the efficacy of the proposed method. As feature ablation progresses, the identifiability of a sensitive medical condition decreases with varying speeds on different diseases. We find that these sensitive diagnoses can be divided into three categories: (1) five diseases have fast declining identifiability (AUC below 0.6 with less than 400 features excluded); (2) seven diseases with progressively declining identifiability (AUC below 0.7 with between 200 and 700 features excluded); and (3) one disease with slowly declining identifiability (AUC above 0.7 with 1,000 features excluded). The fact that the majority (12 out of 13) of the sensitive diseases fall into the first two categories suggests the potential of the proposed feature ablation method as a solution for event-level record privacy protection.

Rich Text Formatted EHR Narratives: A Hidden and Ignored Trove.

This study presents an approach for mining structured information from clinical narratives in Electronic Health Records (EHRs) by using Rich Text Formatted (RTF) records. RTF is adopted by many medical information management systems. There is rich structural information in these files which can be extracted and interpreted, yet such information is largely ignored. We investigate multiple types of EHR narratives in the Enterprise Data Warehouse from a multisite large healthcare chain consisting of both, an academic medical center and community hospitals. We focus on the RTF constructs related to tables and sections that are not available in plain text EHR narratives. We show how to parse these RTF constructs, analyze their prevalence and characteristics in the context of multiple types of EHR narratives. Our case study demonstrates the additional utility of the features derived from RTF constructs over plain text oriented NLP.

Early Prediction of Acute Kidney Injury in Critical Care Setting Using Clinical Notes and Structured Multivariate Physiological Measurements.

The onset of acute kidney injury (AKI) during an intensive care unit (ICU) admission is associated with increased morbidity and mortality. Developing novel methods to identify early AKI onset is of critical importance in preventing or reducing AKI complications. We built and applied multiple machine learning models to integrate clinical notes and structured physiological measurements and estimate the risk of new AKI onset using the MIMIC-III database. From the clinical notes, we generated clinically meaningful word representations and embeddings. Four supervised learning classifiers and mixed-feature deep learning architecture were used to construct prediction models. The best configurations consistently utilized both structured and unstructured clinical features and yielded competitive AUCs above 0.83. Our work suggests that integrating structured and unstructured clinical features can be effectively applied to assist clinicians in identifying the risk of incident AKI onset in critically-ill patients upon admission to the ICU.

Hospital-Based Clinicians' Use of Technology for Patient Care-Related Communication: A National Survey.

OBJECTIVE: To characterize current use of communication technologies, including standard text messaging and secure mobile messaging applications, for patient care-related (PCR) communication. METHODS: We used a Society of Hospital Medicine database to conduct a national cross-sectional survey of hospital-based clinicians. RESULTS: We analyzed data from 620 survey respondents (adjusted response rate, 11.0%). Pagers were provided by hospitals to 495 (79.8%) of these clinicians, and 304 (49%) of the 620 reported they received PCR messages most commonly by pager. Use of standard text messaging for PCR communication was common, with 300 (52.9%) of 567 clinicians reporting receipt of standard text messages once or more per day. Overall, 21.5% (122/567) of respondents received standard text messages that included individually identifiable information, 41.3% (234/567) received messages that included some identifiable information (eg, patient initials), and 21.0% (119/567) received messages for urgent clinical issues at least once per day. About one-fourth of respondents (26.6%, 146/549) reported their organization had implemented a secure messaging application that some clinicians were using, whereas few (7.3%, 40/549) reported their organization had implemented an application that most clinicians were using. DISCUSSION: Pagers remain the technology most commonly used by hospital-based clinicians, but a majority also use standard text messaging for PCR communication, and relatively few hospitals have fully implemented secure mobile messaging applications. CONCLUSION: The wide range of technologies used suggests an evolution of methods to support communication among healthcare professionals.